Mobile elements make up nearly half of the human genome. They are a significant cause of genetic disease as a result of both de novo insertion as well as mediation of nonhomologous recombination and deletion. We propose to build on our previous research to further understand the effects of mobile elements on the generation of genetic diversity in human and non-human primate genomes. We have developed a new technique, based on second-generation high-throughput sequencing, to simultaneously ascertain and genotype all members of mobile-element subfamilies in large samples of individuals. We will apply this technology to 42 large Utah pedigrees to directly estimate, for the first time, the rate of Alu retrotransposition in the human genome. We will also use these pedigrees to explore the relationship between mobile elements and the generation of de novo copy number variants. We will genotype thousands of Alu insertion polymorphisms in a diverse sample of 500 humans. Because our new technique identifies all members of each subfamily, rare insertions will be identified so that an unbiased frequency spectrum of insertion polymorphisms can be analyzed. These data will allow us to search for active Alu elements in the human genome, and they will allow us to test several key hypotheses about ancient human evolutionary history. We will take advantage of the availability of several non-human primate genome sequences to test the effects of mobile elements on insertions and deletions of genomic material during the evolution of these species. We will also examine the roles of mobile elements in mediating transduction events in humans and non-human primates, as this is an important source of new genetic material in genomes.